1. Field of the Invention
This invention relates to a novel method for the production of nuclear substituted cinnamoylanthranilic acid derivatives. More particularly, this invention relates to an improved method for the production of nuclear di-substituted cinnamoylanthranilic acid derivatives which possess strong antiallergic properties and thus are useful for treatment of diseases such as asthma, hay fever, atopic dermatitis and urticaria.
2. Description of the Prior Art
Nuclear substituted cinnamoylanthranilic acid derivatives, especially N-(3,4-dimethoxycinnamoyl)anthranilic acid, are known to exhibit strong antiallergic properties and to be useful for treatment of asthma, hay fever, atopic dermatitis and urticaria, as reported in U.S. Pat. No. 4,070,484; Allergy, 34, 213-219, (1979); and Igaku no Ayumi, 106, No. 8, 576-585 (1978).
Several methods for producing said derivatives have been also disclosed in Japanese patent application Nos. 7359/73, 42273/74, 42465/74, 43673/74, 43678/74, 158554/75, 158555/75, 158556/75, 139368/76, 38555/80, 38556/80 and 8858/81, and in U.S. Pat. No. 3,940,422. Of the methods disclosed in the above patent references, the process described in Japanese patent application No. 8858/81 can be operated with ease and efficiency, and thus this process has advantage for production on an industrial scale. The Japanese patent application No. 8858/81 invention is illustrated by the following preferred process embodiment.
A nuclear unsubstituted or substituted benzaldehyde derivative is heated with a 2-carboxymalonanilic acid derivative at 80.degree.-100.degree. C. for several hours in a solvent medium such as pyridine; or benzene, toluene or xylene (10-20 times by weight the amount of the benzaldehyde derivative or the 2-carboxymalonanilic acid derivative) in the presence of a catalytic amount of a basic compound such as piperidine. The resultant reaction mixture is evaporated and the residue is dissolved in a small amount of an alcohol. The alcoholic solution is poured into ice-water, then hydrochloric acid is added to make the aqueous medium acidic, and the crystalline precipitate which forms is collected by filtration and recrystallized from a suitable organic solvent to yield the desired product.
As apparent from the above described procedure, the process embodiment requires the use of a large volume of pyridine solvent as a reaction medium. This is undesirable because in addition to the cost involved pyridine solvent has the disadvantages of toxicity and odor. Furthermore, since the desired product is obtained as a precipitate from an aqueous acidic solution of the evaporated reaction mixture by acidification with a mineral acid, unreacted materials and byproducts which are insoluble in an aqueous acidic solution are also precipitated, and these components are difficult to remove by recrystallization and thus are contained in the desired product. Hence, the desired product purified by recrystallization always contains such impurities and is not applicable for medicinal purposes without an extensive recrystallization procedure, with a concomitant decrease in product yield.
Accordingly, it is an object of this invention to provide a process for producing anthranilic acid derivatives which is superior to prior art methods such as that described in Japanese patent application No. 8858/81.
It is another object of this invention to provide an improved method for producing nuclear di-substituted cinnamoylanthranilic acid derivatives with a high purity and yield, which derivatives possess strong antiallergic properties and thus are useful for treatment of asthma, hay fever, atopic dermatitis and urticaria.
Other objects and advantages of this invention will become apparent from the accompanying description and examples.